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This article was originally published in The Gray Sheet

Executive Summary

MEDTRONIC'S TRANSVENE LABELING SHOULD INCLUDE DOUBLE-ANCHOR RECOMMENDATION to help guard against lead dislodgment, members of FDA's circulatory system devices advisory panel suggested at an Aug. 2 meeting in Bethesda, Maryland. The group unanimously recommended that FDA approve the Transvene for use with Medtronic's PCD implantable pacer-cardioverter-defibrillator, contingent on several adjustments to labeling. Dislodgment was one of the primary issues addressed during the panel's brief discussion of the Transvene. Eighty percent of dislodgments experienced during clinical trials "occurred within three months of implant," according to Daniel Schaber, Medtronic's manager of tachyarrhythmia and special product clinical evaluation. He noted that at the beginning of the trials, clinical investigators were anchoring the lead with one sleeve. However, the procedure was modified to include use of an additional sleeve. Using the double-anchor approach reduced "the probability of having a dislodgment" from 9.3% to 3.3% at three months, Schaber said. Panel chair Jeffrey Brinker, MD, The Johns Hopkins Hospital, Baltimore, agreed with FDA that if the dislodgment problem was "fixed by the double anchor," the labeling should "firmly" suggest that two anchors be used to secure the leads. However, David Steinhaus, MD, Mid America Heart Institute, Kansas City, Missouri, a clinical investigator for Medtronic, suggested that while "much has been made of" the second sleeve in terms of reducing lead dislodgment, "a lot of it is learning curve experience more than anything." Steinhaus added: "I really don't think it's the second sleeve that really does it. I think it's the fact that you have to get that first sleeve right up next to the vein and you've got to be careful how you tie it down." Steinhaus also noted that sleeve design improvements may have contributed to a decrease in dislodgment. The overall patient survival rate for the PCD/Transvene combination was 93.3% at one year, according to the Transvene premarket approval application data, compared with 88.6% when the PCD was used with epicardial leads. Panel member Debra Echt, MD, Vanderbilt University, Nashville, Tennessee, asked the company for more information on perioperative mortality rates, defined as "deaths that occurred within 30 days post-operatively." Overall perioperative mortality for Transvene recipients was 0.7%. However, in a group of 97 patients who were originally slated for implantation with the Transvene but ultimately received epicardial leads, the rate was much higher at 9.3%, or nine deaths. Seven of those deaths occurred in patients who received epicardial leads the same day they were rejected for Transvene leads. Medtronic investigator Gust Bardy, MD, University of Washington Medical Center, Seattle, explained that when those deaths were reviewed, "it was clear that patients were being put through too much too soon." He recommended delaying "the epicardial for at least two days before proceeding because they have been through a lot if they're failed Transvenes." However, investigator Doug Zipps, Indiana University, Bloomington, disagreed, maintaining that the surgical delay should be a "clinical judgment." Zipps commented that "it's very reasonable to do it at the same time...if one decides early on after just a few [ventricular fibrillation] inductions that the Transvene system is not going to work and immediately goes to a thoracotomy or a subcostal...or whatever." Echt argued that the perioperative mortality figures should be included in the product labeling, saying "there's a huge difference between 0.7% and 9.3% and maybe we ought to be a little bit stronger about informing that this really is associated with a high perioperative mortality even though there may be individual patients in whom it's perfectly safe. . . I think that people should be aware of this 9.3 number." Medtronic, which noted that there is a warning in the labeling, agreed also to include the figure in the package insert. The panel also suggested cautioning physicians not to place Transvene leads too close to standard pacemaker leads already implanted in a patient. Zipps noted that in the two Transvene patients he treated who were already implanted with standard pacemaker leads, he was "able to place the electrode such that the size of the spike was sufficiently small in terms of what was sensed by the PCD that it was not a problem, and the spikes did not inhibit PCD function in the event of a ventricular tachycardia or fibrillation, both of which were induced in the patient during pacing to be certain that nothing would happen." Reacting to panel commentary, Medtronic offered to include in the labeling a statement indicating that Transvene and standard leads should be "separated as far as possible while still maintaining appropriate function of the pacemaker." Other panel recommendations included the addition of electrode and polarity configuration diagrams and a warning against using the stiff subcutaneous patch on the epicardium. Panel member Gabriel Gregoratos, MD, University of California at Davis, "was a bit disappointed to find out that the mean hospital stay was only three days less for a transvenous system" than for patients implanted with epicardial leads, or seven days as opposed to 10. Steinhaus replied that "one of the major benefits of the device" is the decreased discomfort in patients, who may "be up doing what they want to do very, very quickly." He also said that he "[sends] patients home now routinely at two days" and that "for the purposes of the study, we were being pretty conservative." The panel also discussed whether the transvenous leads could be used with other manufacturers' products. Noting that the Transvene is "carefully" labeled for use only with the PCD, Brinker, for example, commented that "it's unfortunate that we haven't reached the state of evolution between and betwixt manufacturers of pacemaker leads" such that the leads are compatible with other manufacturers' devices and vice versa. Medtronic's Schaber told the panel that the firm "is moving toward that with a VF1 standard," which would make various manufacturers' leads and ICDs compatible. Such a standard already exists for pacemakers. Medtronic, which says it would try to be "responsive" to medical community demands for compatibility, expects the industry to design a standard connector interface at the device end. Schaber told the panel, however, that safety and efficacy data must be compiled before it "can recommend any lead to be used with one of" Medtronic's devices. The approvable recommendation for Transvene moves Medtronic one step closer to being the first company to market in the U.S. a transvenous lead system in conjunction with a third-generation implantable defibrillator. Medtronic's third-generation device, the PCD, was approved in February ("The Gray Sheet" Feb. 15, p. 3). Lilly's Cardiac Pacemakers Inc. division has a transvenous lead, the Endotak, close to approval; the firm recently received an "approvable" letter from FDA for the device, which is indicated for use with CPI's Ventak and Ventak P ("The Gray Sheet" Aug. 2, In Brief). The company's Ventak PRx third-generation implantable defibrillator also was reviewed by the circulatory system device panel on Aug. 2 and deemed approvable; however, CPI says that it has not yet submitted data to FDA on use of the Endotak with the PRx. Ventritex, which began shipping its third generation Cadence device in May ("The Gray Sheet" May 10, p. 3), plans to request an investigational device exemption for a companion transvenous lead system in the third quarter.

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